A wide variety of skin care preparations are currently available. There are currently available several preparations for the treatment of cellulite, a dimpling of the skin over excess superficial fat deposits, but these are believed to have doubtful efficacy. A wide variety of medically useful skin preparations are also currently available, comprising primarily glucocorticoids and retinoid topical medicaments, both of which have varying side-effects and usefulness. There is a considerable number of skin conditions and diseases such as stria, cellulite, roughened skin, actinic skin damage, intrinsically aged skin, photodamaged skin, lichen planus, ichtyosis, acne, psoriasis, wrinkled skin, eczema, seborrhoeic dermatitis, scleroderma, hyperkeratinizing disorders, keloids and skin scarring.
Eczema (dermatitis) is an itchy inflammation of the superficial skin layers caused by an outside agent or by endogenous factors. The terms dermatitis and eczema are used interchangeably.
The obvious treatment of eczema is to try to avoid precipitating factors.
Additionally, eczema is usually treated with topical steroids such as hydrocortisone, clobetasone butyrate, betamethasone and clobetasol propionate. The side effects of steroid use, particularly in the long term are well known and consist of skin atrophy, risk for systemic absorption of the drug and rebound phenomena when the drug is withdrawn.
There is a need for improved or alternate compositions for the treatment of dermatitis skin conditions such as psoriasis and eczema. New principles for treating eczema in particular should aim at reducing the reactivity of cutaneous cells, inhibiting cytokine release and improving the epidermal barrier recovery.
The structurally similar thyroid hormone compounds (3,3',5 -triiodo-L-thyronine) triiodothyronine (T.sub.3) and thyroxine L-thyroxine (T.sub.4) have a very wide range of effects. In adult mammals they influence nearly all organs, the metabolism of nutrients, basal metabolic rate and oxygen consumption. In humans, the deficiency or excess of circulating thyroid hormone compounds results in the well characterised syndromes, hypo- and hyperthyroidism. Small concentrations of thyroid hormone metabolites which are also endocrinologically active exist. Among these thyroid hormone compounds are tri-iodothyroacetic acid("Triac" [4-(4-hydroxy-3-iodophenoxy)-3,5-diiodophenyl])acetic acid) and tri-iodoproprionic acid ("Tri-prop"[4-(4-hydroxy-3-iodophenoxy)-3,5-diiodophenyl]propionic acid).
Thyroid hormone compounds exert many of their actions by binding to a family of receptor proteins termed the C-erb-A family. In humans, this receptor protein family is now known to comprise several members, notably the human thyroid receptor alpha-1, the human thyroid receptor alpha-2 which binds the hormone poorly or not at all, the human thyroid receptor .beta.-1, and the human thyroid receptor .beta.-2. These proteins are part of a larger superfamily of steroid hormone receptors which comprises the glucocorticoid receptors, the retinoic acid receptors, the vitamin D receptors, and the insect moulting receptors--the receptors for ecdysone and the insect juvenile hormone compounds. Receptors for thyroid hormones are found in human skin, human fibroblasts and keratinocytes and they are also found in all other tissues within the human body (1).
In addition to the naturally occurring thyroid hormone compounds, a large number of chemical compounds which bind to the thyroid hormone receptor and which produce thyroid hormone-like effects have been synthesized see for example U.S. Pat. No. 5,401,772. For the purpose of this patent, the class of chemical entity which can act as a thyroid hormone compound but are not naturally occuring is defined herein as a `thyroid-like compound`.
Thyroid hormone compounds, in many cases, act indirectly by influencing the effects of other hormones and tissues (1). For example in the rat, thyroid administration increases pituitary growth hormone production which in turn affects hepatic protein production including that of alpha-2 euglobulin. Functionally, in the rat, growth hormone may act as a second message for thyroid hormone(1). The biology of thyroid hormone compounds has been extensively studied after oral administration, which makes the relationship between a direct effect of thyroid hormone compounds and an indirect effect mediated by thyroid hormone modulation of other autocrine, paracrine or endocrine factors difficult to ascertain.
Orally administered thyroid hormone (T.sub.4) influence the connective tissue biology of the skin. When given orally, thyroid hormone (T.sub.4) induce an increase in neutral salt and acid soluble collagen, but decrease insoluble collagen in the skin of guinea pigs (2). Fibronectin production is decreased in human fibroblasts and fibroblast glycosoaminoglycans are either decreased or unchanged depending on the experimental conditions used (3,4,5,7,7a). Keratin gene expression for both the basal cell keratin K5 and K14 genes and the differentiation specific K10 gene is negatively regulated by thyroid hormones (9,8) in keratinocyte culture. These effects are mirrored by similar cell culture responses to retinoic acid (9) or the retinoid Tretinoin (19).
Histological studies of skin from individuals who have an excess of thyroid hormone compounds show an increased number of cell layers in the skin, reflected by mean epidermal cell number, increased protein turnover with increased proline incorporation and generalized increases in epidermal proliferation compared to normal skin (11). In individuals who have a lack of thyroid hormone compounds, the skin is atrophic with thinning of the epidermis and a decrease in cellularity. In human clinical biology, thyroid hormone excess leads to a general smoothing of the skin and the loss of wrinkles especially over the olecranon (elbow) surface.
Thyroid hormone compounds also accelerate fat synthesis and lipolysis (breakdown). In rats which have an excess of thyroid hormone compounds either chemically or by natural means, fat stores are in general decreased (12,13), although in humans clinical observation of thyroid hormone compound excess discloses either in increase of decrease in weight. The synthesis of fats may be increased (14,15) or decreased (12,13,16,21). Attempts to utilize the effects of excess oral thyroid hormone for weight loss in humans have in general failed because of severe adverse side effects (25,26).
Orally given thyroid hormone compounds in excess of normal bodily requirements or medical conditions which are associated with excess thyroid hormone compounds such as Grave's disease or toxic nodular goitre produce an acceleration of heart beat with associated heart failure, cardiac arrhythmias, osteoporosis, increased intestinal motility leading to diarrhoea, psychiatric abnormalities, and an increase in the basal metabolic rate. Attempts to use oral thyroid hormone compounds for diminishing lipid levels in man resulted in increased cardiac deaths (17).
RO76691 and 76692 respectively disclose an anti-wrinkle cream comprising a crude preparation from animal endocrine glands, including the thyroid gland, and a method of obtaining lipoid extracts from animal byproducts respectively. No data on the efficacy of the anti-wrinkle cream is provided nor is the thyroid hormone content of the cream provided or even mentioned. In particular, there is no suggestion in those patents of the efficacy of the compositions, methods, and uses of the present invention.
The use of Triac and its salts for a reduction of cellulite is disclosed in FR 2.153.202 (7134447). FR2197577 (72.30781) discloses various derivatives of Triac, including para hydroxy esters thereof, as having utility for the same indication. EP060776 discloses activity of an isopropyl derivative of Triac for the same indication. CH642851 (1168/80) discloses the utility of a liposome formulation of Triac together with glycosoaminoglycans for reducing cellulite. GB1354263 also discloses the use of Triac itself for reducing fat deposits. GB1400851 relates to the synthesis of ethyl esters and alkyl carboxy acids derivatives of Triac and their use in reducing cellulite in combination with leeches, hyaluronidase, proteases, and lipase.
None of the above publications disclose or suggest the usefulness of compounds selected from those that bind the thyroid hormone receptor. The relationship between Triac and thyroid hormones is not made in any of these patents and no data is presented to show the relationship of the above mentioned compounds to the thyroid hormone dependent endocrine system via an effect mediated through the human thyroid receptor. In fact, FR2354101 discloses the use of Triac as an inhibitor of phosphodiesterase and its effect to increase cyclic AMP. This effect occurs only at dose ranges of approximately 10.sup.-4 M in in vitro experiments using isolated adipocytes. In concert with this mode of activity, the prior art literature makes claims for effective concentrations of chemical entity for anti-cellulite effects as greater than 50 mg of Triac or Triac derivative per 100 ml of vehicle and usually between 100 and 200 mg/100 gms of excipient.
FR96.171 discloses the topical cellular growth accelerating activity and mitogenic of thyroxine (0.001-0.008 mg. %) in a propylene glycol diethyl ether vehicle in rat skin. No mention is made of other compounds which have thyroid hormone receptor binding activity such as Triac or Tri-iodothyronine, or other thyromimetic compounds known at the time (Journal of Medicinal Chemistry, 6, p 554-563, 1963). No teaching concerning the effects of thyroid hormone receptor binding entities on epidermal differentiation, gene expression or keratinization is made. GB782,745 and 859,546 describe the topical usefulness of compounds of a class which partially overlap with chemical entities which bind to the thyroid hormone receptor, but includes compounds including L-T-1 with no thyroid hormone receptor binding activity, and only a small subset of compounds which do recognize the receptor. In these patents, no claims are made for chemical entities characterized by binding to the thyroid hormone receptor or having thyroid hormone like activity. U.S. Pat. No. 3,198,702 discloses a method of treating bums comprising the topical application of certain thyroxin analogues which are a subset of the same class of compounds claimed to have activity in GB 782745 and 859546.
No prior art document discloses the skin differentiating and collagen promoting effects of thyroid hormone or its analogues.